Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds

ABSTRACT

Methods useful for preparing compounds of formula I: 
     
       
         
         
             
             
         
       
     
     and salts thereof are disclosed. Also disclosed are intermediates useful in the preparation of such compounds.

This application claims priority to U.S. provisional application No.60/957,744, filed Aug. 24, 2007, the entirety of which is incorporatedherein by reference.

1. FIELD OF THE INVENTION

This invention relates to methods of making4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds.

2. BACKGROUND

Certain 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-basedcompounds are inhibitors of the enzyme tryptophan hydroxylase (TPH),which catalyzes the rate limiting step of serotonin's biosynthesis. See,U.S. patent application Ser. Nos. 11/638,677 and 60/874,596, both filedDec. 12, 2006. It is believed that these compounds may be used to treata wide range of diseases and disorders associated with the serotonergicsystem. Id. Consequently, efficient methods of their manufacture aredesired.

3. SUMMARY OF THE INVENTION

This invention encompasses methods of preparing compounds of formula I:

and salts thereof, the various substituents of which are defined herein.When administered to mammals, preferred compounds of this formulainhibit TPH (e.g., TPH1), and may be useful in the treatment of variousdiseases and disorders.

This invention also encompasses intermediates that are useful in thesynthesis of compounds of formula I.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an X-ray diffraction pattern of a crystalline solid form of(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.The pattern was obtained using a Rigaku MiniFlex diffractometer (Cu(1.54060 Å) radiation).

FIG. 2 is an X-ray diffraction pattern of a crystalline solid form of1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone.The pattern was obtained using a Rigaku MiniFlex diffractometer (Cu(1.54060 Å) radiation).

FIG. 3 is an X-ray diffraction pattern of a crystalline solid form of1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole. The pattern wasobtained using a Rigaku MiniFlex diffractometer (Cu (1.54060 Å)radiation).

5. DETAILED DESCRIPTION

This invention is based on the discovery of novel methods of preparingcompounds of formula I and intermediates useful therein. Whenadministered to mammals, preferred compounds of formula I inhibit TPH,and may be used in the treatment of a variety of diseases and disorders.See generally, U.S. patent application Ser. Nos. 11/638,677 and60/874,596, both filed Dec. 12, 2006.

5.1. DEFINITIONS

Unless otherwise indicated, the term “alkenyl” means a straight chain,branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or2 to 6) carbon atoms, and including at least one carbon-carbon doublebond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and3-decenyl.

Unless otherwise indicated, the term “alkoxy” means an —O-alkyl group.Examples of alkoxy groups include —OCH₃, —OCH₂CH₃, —O(CH₂)₂CH₃,—O(CH₂)₃CH₃, —O(CH₂)₄—CH₃, —O(cyclopenyl) and —O(CH₂)₅CH₃. The term“lower alkoxy” refers to —O-(lower alkyl).

Unless otherwise indicated, the term “alkyl” means a straight chain,branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20(e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to4 carbons are referred to as “lower alkyl.” Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl,pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkylmoieties may be monocyclic or multicyclic, and examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.Additional examples of alkyl moieties have linear, branched and/orcyclic portions (e.g., 1-ethyl-4-methyl-cyclohexyl). The term “alkyl”includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.

Unless otherwise indicated, the term “alkylaryl” or “alkyl-aryl” meansan alkyl moiety bound to an aryl moiety.

Unless otherwise indicated, the term “alkylheteroaryl” or“alkyl-heteroaryl” means an alkyl moiety bound to a heteroaryl moiety.

Unless otherwise indicated, the term “alkylheterocycle” or“alkyl-heterocycle” means an alkyl moiety bound to a heterocycle moiety.

Unless otherwise indicated, the term “alkynyl” means a straight chain,branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2to 6) carbon atoms, and including at least one carbon-carbon triplebond. Representative alkynyl moieties include acetylenyl, propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl,6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl,8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.

Unless otherwise indicated, the term “aryl” means an aromatic ring or anaromatic or partially aromatic ring system composed of carbon andhydrogen atoms. An aryl moiety may comprise multiple rings bound orfused together. Examples of aryl moieties include anthracenyl, azulenyl,biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl,1,2,3,4-tetrahydro-naphthalene, and tolyl.

Unless otherwise indicated, the term “arylalkyl” or “aryl-alkyl” meansan aryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the terms “biohydrolyzable amide,”“biohydrolyzable ester,” “biohydrolyzable carbamate,” “biohydrolyzablecarbonate,” “biohydrolyzable ureido” and “biohydrolyzable phosphate”mean an amide, ester, carbamate, carbonate, ureido, or phosphate,respectively, of a compound that either: 1) does not interfere with thebiological activity of the compound but can confer upon that compoundadvantageous properties in vivo, such as uptake, duration of action, oronset of action; or 2) is biologically inactive but is converted in vivoto the biologically active compound. Examples of biohydrolyzable estersinclude lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkylesters, and choline esters. Examples of biohydrolyzable amides includelower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkyl-carbonyl amides. Examples of biohydrolyzable carbamatesinclude lower alkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

Unless otherwise indicated, the terms “halogen” and “halo” encompassfluorine, chlorine, bromine, and iodine.

Unless otherwise indicated, the term “heteroalkyl” refers to an alkylmoiety (e.g., linear, branched or cyclic) in which at least one of itscarbon atoms has been replaced with a heteroatom (e.g., N, O or S).

Unless otherwise indicated, the term “heteroaryl” means an aryl moietywherein at least one of its carbon atoms has been replaced with aheteroatom (e.g., N, O or S). Examples include acridinyl,benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl,benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl,indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, andtriazinyl.

Unless otherwise indicated, the term “heteroarylalkyl” or“heteroaryl-alkyl” means a heteroaryl moiety bound to an alkyl moiety.

Unless otherwise indicated, the term “heterocycle” refers to anaromatic, partially aromatic or non-aromatic monocyclic or polycyclicring or ring system comprised of carbon, hydrogen and at least oneheteroatom (e.g., N, O or S). A heterocycle may comprise multiple (i.e.,two or more) rings fused or bound together. Heterocycles includeheteroaryls. Particular heterocycles are 5- to 13-membered heterocyclescontaining 1 to 4 heteroatoms selected from nitrogen, oxygen, andsulphur. Others are 5- to 10-membered heterocycles containing 1 to 4heteroatoms selected from nitrogen, oxygen, and sulphur. Examples ofheterocycles include benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl,cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl,piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl andvalerolactamyl.

Unless otherwise indicated, the term “heterocyclealkyl” or“heterocycle-alkyl” refers to a heterocycle moiety bound to an alkylmoiety.

Unless otherwise indicated, the term “heterocycloalkyl” refers to anon-aromatic heterocycle.

Unless otherwise indicated, the term “heterocycloalkylalkyl” or“heterocycloalkyl-alkyl” refers to a heterocycloalkyl moiety bound to analkyl moiety.

Unless otherwise indicated, the term “prodrug” encompassespharmaceutically acceptable esters, carbonates, thiocarbonates, N-acylderivatives, N-acyloxyalkyl derivatives, quaternary derivatives oftertiary amines, N-Mannich bases, Schiff bases, amino-acid conjugates,phosphate esters, metal salts and sulfonate esters of compoundsdisclosed herein. Examples of prodrugs include compounds that comprise abiohydrolyzable moiety (e.g., a biohydrolyzable amide, biohydrolyzablecarbamate, biohydrolyzable carbonate, biohydrolyzable ester,biohydrolyzable phosphate, or biohydrolyzable ureide analog). Prodrugsof compounds disclosed herein are readily envisioned and prepared bythose of ordinary skill in the art. See, e.g., Design of Prodrugs,Bundgaard, A. Ed., Elseview, 1985; Bundgaard, hours., “Design andApplication of Prodrugs,” A Textbook of Drug Design and Development,Krosgaard-Larsen and hours. Bundgaard, Ed., 1991, Chapter 5, p. 113-191;and Bundgaard, hours., Advanced Drug Delivery Review, 1992, 8, 1-38.

Unless otherwise indicated, the term “protecting group” or “protectivegroup,” when used to refer to part of a molecule subjected to a chemicalreaction, means a chemical moiety that is not reactive under theconditions of that chemical reaction, and which may be removed toprovide a moiety that is reactive under those conditions. Protectinggroups are well known in the art. See, e.g., Greene, T. W. and Wuts, P.G. M., Protective Groups in Organic Synthesis (3^(rd) ed., John Wiley &Sons: 1999); Larock, R. C., Comprehensive Organic Transformations(2^(nd) ed., John Wiley & Sons: 1999). Some examples include benzyl,diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl,and pthalimido.

Unless otherwise indicated, the term “pseudohalogen” refers to apolyatomic anion that resembles a halide ion in its acid-base,substitution, and redox chemistry, generally has low basicity, and formsa free radical under atom transfer radical polymerization conditions.Examples of pseudohalogens include azide ions, cyanide, cyanate,thiocyanate, thiosulfate, sulfonates, and sulfonyl halides.

Unless otherwise indicated, the term “stereomerically enrichedcomposition of” a compound refers to a mixture of the named compound andits stereoisomer(s) that contains more of the named compound than itsstereoisomer(s). For example, a stereoisomerically enriched compositionof (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and(R)-butan-2-ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10,95/5, and 98/2.

Unless otherwise indicated, the term “stereoisomeric mixture”encompasses racemic mixtures as well as stereomerically enrichedmixtures (e.g., R/S=30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and70/30).

Unless otherwise indicated, the term “stereomerically pure” means acomposition that comprises one stereoisomer of a compound and issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure composition of a compound having one stereocenterwill be substantially free of the opposite stereoisomer of the compound.A stereomerically pure composition of a compound having twostereocenters will be substantially free of other diastereomers of thecompound. A stereomerically pure composition of a compound that hasmultiple stereocenters, but which is drawn or named in such a way thatthe stereochemistries of less than all of its stereocenters are defined,is substantially free of the isomers of the compound that have differentstereochemistries at the stereocenters for which stereochemistry isdefined. For example, “stereomerically pure((1R)-1,2-dichloropropyl)benzene” refers to((1R)-1,2-dichloropropyl)benzene that is substantially free of((1S)-1,2-dichloropropyl)benzene.

A typical stereomerically pure compound comprises greater than about 80%by weight of one stereoisomer of the compound and less than about 20% byweight of other stereoisomers of the compound, greater than about 90% byweight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound, or greater thanabout 99% by weight of one stereoisomer of the compound and less thanabout 1% by weight of the other stereoisomers of the compound.

Unless otherwise indicated, the term “substituted,” when used todescribe a chemical structure or moiety, refers to a derivative of thatstructure or moiety wherein one or more of its hydrogen atoms issubstituted with an atom, chemical moiety or functional group such asalcohol, aldehyde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl(e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy(—OC(O)alkyl), amide (—C(O)NH-alkyl- or -alkylNHC(O)alkyl), amidinyl(—C(NH)NH-alkyl- or —C(NR)NH₂), amine (primary, secondary and tertiarysuch as alkylamino, arylamino, arylalkylamino), aroyl, aryl, aryloxy,azo, carbamoyl (—NHC(O)O-alkyl- or —OC(O)NH-alkyl), carbamyl (e.g.,CONH₂, as well as CONH-alkyl, CONH-aryl, and CONH-arylalkyl), carbonyl,carboxyl, carboxylic acid, carboxylic acid anhydride, carboxylic acidchloride, cyano, ester, epoxide, ether (e.g., methoxy, ethoxy),guanidino, halo, haloalkyl (e.g., —CCl₃, —CF₃, —C(CF₃)₃), heteroalkyl,hemiacetal, imine (primary and secondary), isocyanate, isothiocyanate,ketone, nitrile, nitro, oxygen (i.e., to provide an oxo group),phosphodiester, sulfide, sulfonamido (e.g., SO₂NH₂), sulfone, sulfonyl(including alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl),sulfoxide, thiol (e.g., sulfhydryl, thioether) and urea(—NHCONH-alkyl-).

Unless otherwise indicated, the phrase “greater than X,” where X is anumber, has the same meaning as “X or greater than X.” Similarly, thephrase “greater than about X,” where X is a number, has the same meaningas “about X or greater than about X.”

Unless otherwise indicated, the phrase “less than X,” where X is anumber, has the same meaning as “X or less than X.” Similarly, thephrase “less than about X,” where X is a number, has the same meaning as“about X or less than about X.”

Unless otherwise indicated, the phrase “between X and Y” encompassesvalues between X and Y as well as X and Y themselves. Similarly, thephrases “between about X and about Y” and “between about X and Y” bothrefer to values between about X and about Y, including about X and aboutY.

Unless otherwise indicated, the term “include” has the same meaning as“include” and the term “includes” has the same meaning as “includes, butis not limited to.” Similarly, the term “such as” has the same meaningas the term “such as, but not limited to.”

Unless otherwise indicated, one or more adjectives immediately precedinga series of nouns is to be construed as applying to each of the nouns.For example, the phrase “optionally substituted alky, aryl, orheteroaryl” has the same meaning as “optionally substituted alky,optionally substituted aryl, or optionally substituted heteroaryl.”

Unless otherwise indicated, a structure or name of a compound or genusof compounds encompasses all forms of that compound or genus ofcompounds, and all compositions comprising that compound or genus ofcompounds.

It should be noted that a chemical moiety that forms part of a largercompound may be described herein using a name commonly accorded it whenit exists as a single molecule or a name commonly accorded its radical.For example, the terms “pyridine” and “pyridyl” are accorded the samemeaning when used to describe a moiety attached to other chemicalmoieties. Thus, the two phrases “XOH, wherein X is pyridyl” and “XOH,wherein X is pyridine” are accorded the same meaning, and encompass thecompounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.

It should also be noted that if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or the portion of the structure is to beinterpreted as encompassing all stereoisomers of it. Similarly, names ofcompounds having one or more chiral centers that do not specify thestereochemistry of those centers encompass pure stereoisomers andmixtures thereof. Moreover, any atom shown in a drawing with unsatisfiedvalences is assumed to be attached to enough hydrogen atoms to satisfythe valences. In addition, chemical bonds depicted with one solid lineparallel to one dashed line encompass both single and double (e.g.,aromatic) bonds, if valences permit.

5.2. METHODS OF SYNTHESIS

This invention encompasses methods of preparing compounds of formula I:

and salts (e.g., pharmaceutically acceptable salts) thereof, wherein: A₁is optionally substituted heterocycle; each R₁ is independently amino,halogen, hydrogen, C(O)R_(A), OR_(A), NR_(B)R_(C), S(O₂)R_(A), oroptionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; R₂ isindependently amino, halogen, hydrogen, C(O)R_(A), OR_(A), NR_(B)R_(C),S(O₂)R_(A), or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; R₃ is hydrogen, C(O)R_(A), C(O)OR_(A), or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;R₄ is hydrogen or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; each R_(A) is independentlyhydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R_(B) is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R_(C) isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; and m is 1-4.

In certain embodiments of the invention, A₁ is aromatic; in others, itis not. In others, A₁ is optionally substituted with one or more ofhalogen or lower alkyl.

In some, the compound of formula I is of formula I(a):

In particular embodiments, the compound of formula I(a) is formula I(b):

wherein: each R₅ is independently amino, halogen, hydrogen, C(O)R_(A),OR_(A), NR_(B)R_(C), S(O₂)R_(A), or optionally substituted alkyl,alkyl-aryl or alkyl-heterocycle; and n is 1-3.

In some embodiments, R₁ is hydrogen or halogen. In some, m is 1. Insome, R₂ is hydrogen or amino. In some, R₃ is hydrogen or lower alkyl.In some, R₃ is C(O)OR_(A) and R_(A) is alkyl. In some, R₄ is hydrogen orlower alkyl. In some, R₅ is hydrogen or lower alkyl (e.g., methyl). Insome, n is 1.

A particular compound of formula I(b) is(S)-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid:

Another compound of formula I(b) is (S)-ethyl3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoate:

Another compound of formula I(b) is (S)-ethyl2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate:

In one embodiment of the invention, the compound of formula I isprepared according to the general approach shown below in Scheme 1:

wherein Y₁ is halogen or pseudohalogen. Here, a compound of formula IIis contacted with one of formula III under suitable reaction conditions.Such conditions include the use of a base (e.g., alkyllithium,alkylmagnesium, alkoxides, alkaline metal hydroxides, alkaline metalphosphates, and alkaline metal carbonates), a temperature of from about50 to about 150° C., a reaction time of from about 10 to about 40 hours,and polar aprotic solvents. A particular base is cesium carbonate.

In certain embodiments, the compound of formula II is of formula II(a):

In some such compounds, R₁ is chloro and m is 1. A particular compoundis(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol:

A particular crystalline form of this compound has a melting point ofabout 120° C. as measured by differential scanning calorimetry (DSC)(onset temperature). In this context, the term “about” means±5.0° C. Theform provides a X-ray powder diffraction (XRPD) pattern with peaks atone or more of about 9.9, 11.0, 19.2, 19.9, 24.4, 30.0, 31.0 and/or 40.4degrees 2θ. In this context, the term “about” means±0.3 degrees. Asthose skilled in the art are well aware, the relative intensities ofpeaks in a X-ray diffraction pattern of a crystalline form can varydepending on how the sample is prepared and how the data is collected.With this in mind, an example of a XRPD pattern of this crystalline formis provided in FIG. 1.

Compounds of formula II can be prepared by reducing compounds of formulaIV:

using methods generally known as Noyori hydrogenation and Noyoritransfer hydrogenation. In a particular method, the reduction isachieved using a platinum group metal (e.g., iridium, ruthenium,rhodium) catalyst with a Noyori-type chiral ligand, such as(1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine.

A particular compound of formula IV is1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone:

A particular crystalline form of this compound has a melting point ofabout 83° C. as measured by DSC (onset temperature). In this context,the term “about” means±5.0° C. The form provides a XRPD pattern withpeaks at one or more of about 8.1, 11.3, 16.3, 22.7 and/or 27.3 degrees2θ. In this context, the term “about” means±0.3 degrees. An example of aXRPD pattern of this crystalline form is provided in FIG. 2.

Compounds of formula IV can be prepared from compounds of formula V:

wherein X is bromine or iodine. For example, a compound of formula V canbe reacted with an alkyllithium or alkylmagnesium reagent to form thecorresponding lithium or magnesium compound, which can then be reactedwith ethyl 2,2,2-trifluoroacetate. Particular alkyl lithium reagentsinclude n-butyllithium, sec-butyllithium, and t-butyllithium. Particularmagnesium reagents include isopropyl magnesium chloride andtributylmagnesium chloride. Suitable reaction conditions includetemperatures of from about −80 to about 40° C., reaction times of fromabout 10 minutes to about 10 hours, and aprotic solvents. Thus, thecompoundI-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanonecan be prepared from 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole:

A particular crystalline form of this compound has a melting point ofabout 76° C. as measured by DSC (onset temperature). In this context,the term “about” means±5.0° C. The form provides a X-ray powderdiffraction (XRPD) pattern with peaks at about 8.2, 16.4, 17.3, 19.0,22.7, 25.8, 28.4, 31.0 and/or 33.6 degrees 2θ. In this context, the term“about” means±0.3 degrees. An example of a XRPD pattern of thiscrystalline form is provided in FIG. 3.

Compounds of formula III can be prepared by coupling a compound offormula III(a):

with 2-amino-4,6-dichloropyrimidine, wherein each R′ is independentlyhydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle,aryl, or heterocycle, or are taken together with the oxygen atoms towhich they are attached to provide a cyclic dioxaborolane. SuitableSuzuki coupling conditions are well known in the art, and include theuse of a palladium catalyst. Examples of palladium catalysts includebis(triphenylphosphine)-palladium(II) chloride, mixture of a palladiumsalt, such as palladium chloride or palladium acetate, and a ligand,such as triphenylphosphine, dihydrogendichlorobis(di-tert-butylphosphinito-kP)palladate(2-) (POPd), dihydrogendi-μ-chlorotetrakis(di-tert-butylphosphinito-kP)dipalladate(2-) (POPd1),dihydrogendi-μ-chlorodichlorobis(di-tert-butylphosphinito-kP)dipalladate(2-)(POPd2), dihydrogendichlorobis(tert-butylcyclohexylphosphinito-kP)palladate(2-) (POPd3),dihydrogendi-μ-chlorodichlorobis(tert-butylcyclohexylphosphinito-kP)dipalladate(2-)(POPd4), dihydrogendi-μ-chlorotetrakis(tert-cyclohexylphosphinito-kP)dipalladate(2-)(POPd5), dihydrogendi-μ-chlorodichlorobis(dicyclohexylphosphinito-kP)dipalladate(2-)(POPd6), dihydrogendi-μ-chlorotetrakis(dicyclohexylphosphinito-kP)dipalladate(2-) (POPd7),dichlorobis(chlorodi-tert-butylphosphine)palladium(II) (PXPd),dichloro(chlorodi-tert-butylphosphine)palladium(II) dimer (PXPd2),dibromo(chlorodi-tert-butylphosphine)palladium(II) dimer (PXPd2-Br),dichlorobis(chloro-tert-butylcyclohexylphosphine)palladium(II) (PXPd3),dichloro(chloro-tert-butylcyclohexylphosphine)palladium(II) dimer(PXPd4), dichloro(chlorodicyclohexylphosphine)palladium(II) dimer(PXPd6), and dichlorobis(chlorodicyclohexylphosphine)palladium(II)(PXPd7). In one embodiment, the catalyst is notbis(triphenylphosphine)-palladium(II) chloride.

In one embodiment, the compound of formula III(a) is of the formula:

Compounds disclosed herein can be crystallized alone or with othercompounds (e.g., amino acids) to provide co-crystals. Thus, oneembodiment of the invention encompasses a method of forming a co-crystalof a compound of formula I, which comprises contacting a compound offormula I with a pharmaceutically acceptable amino acid under conditionssufficient to provide a co-crystal of the compound of formula I and theamino acid.

6. EXAMPLES 6.1. Preparation of1-(4-Chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone

A 3L 3-neck round bottom flask equipped with a mechanical stirrer, atemperature controller, and a nitrogen inlet was charged with potassiumtert-butoxide (Aldrich 95%, 84.6 g, 0.716 mol) and DMSO (400 mL, 4×) atroom temperature and stirred for 15 minutes. To this solution was addedpyrazole 2 (59 g, 0.719 mol) followed by a DMSO rinse (50 mL, 0.5×). Theresulting orange turbid solution was stirred for 15 minutes and fluoride1 (100 g, 0.477 mol) was added followed by a DMSO rinse (50 mL, 0.5×).This mixture was then heated to 50° C. and held for 5 hours at thistemperature. After cooling to room temperature, the reaction mixture wasdiluted with MTBE (750 mL), and water (500 mL) was added to give a brownturbid mixture. After 15 minutes stirring, the organic layer wasseparated and sequentially washed with 1 N HCl (250 mL), brine (250 mL),and water (250 mL). Solution assay of organic layer was carried outusing GC (conversion >99%, solution yields of 3 and its regioisomer 4were 83% and 17%, respectively). The MTBE solution was then concentratedunder vacuum to a total volume of about 200 mL (KF showed 0.737% water).THF (500 mL) was added, and concentrated to 2× solution (KF=0.158%). THFaddition-concentration sequence was repeated to give a 2× solution(KF=0.023%), which used directly in the next step.

Analytical samples of compounds 3 and 4 were purified by columnchromatography and characterized: Compound 3: white crystals; M.p.: 76°C. (DSC onset temperature). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (1H, d, J=2.3Hz), 7.61 (1H, d, J=8.6 Hz), 7.58 (1H, d, J=2.5 Hz), 7.22 (1H, dd,J=8.6, 2.6 Hz), 6.27 (1H, d, J=2.5 Hz), 2.38 (3H, s); ¹³C NMR (100 MHz,CDCl₃) δ 150.8, 140.6, 134.6, 134.1, 132.0, 129.0, 128.2, 115.4, 107.0,13.6. Compound 4: white crystals; ¹H NMR (400 MHz, CDCl₃) δ 7.65 (1H, d,J=8.6 Hz), 7.62 (1H, d, J=1.5 Hz), 7.43 (1H, d, J=2.5 Hz), 7.35 (1H, dd,J=8.6, 2.2 Hz), 6.21 (1H, s), 2.19 (3H, s); ¹³C NMR (100 MHz, CDCl₃) δ140.6, 140.2, 140.0, 134.1, 133.9, 130.8, 130.2, 120.7, 105.9, 11.4.

The above THF solution was transferred to a jacketed 3L 3-neck roundbottom flask equipped with a mechanical stirrer, a temperaturecontroller, and a nitrogen inlet. After diluting with THF (800 mL), thewater content in the solution was checked by KF (0.053%). To the abovesolution was added a solution of i-PrMgCl in THF (Aldrich 2 M, 286 mL,0.572 mol) at 0-10° C. over 1 hours. The resulting solution was stirredfor 30 minutes at 10° C. (GC showed the completion of magnesium-bromineexchange reaction). Ethyl trifluoroacetate (74 mL, 0.620 mol) was thenadded to the Grignard solution between −20 and −10° C. over 45 minutes,slowly warmed to 0° C., and stirred for 30 minutes at the sametemperature. The reaction mixture was poured into 2 N HCl (300 mL) at 0°C., and stirred for 30 minutes at room temperature. The organic layerwas diluted with MTBE (500 mL), and washed with brine (250 mL) followedby water (250 mL). Solution assay of organic layer was carried out usingGC (Compound 5: 67% solution yield, the corresponding regioisomer 6 waspresent at about 20% relative to 5). The solution was then concentratedunder vacuum to 2× solution. To remove water, THF (500 mL) was added,and evaporated to 2× solution. THF addition-concentration was repeatedto give a 2× solution. Heptane (500 mL) was added, concentrated to 2×solution to exchange the solvent for recrystallization. Heptane (500 mL)was again added, concentrated to 3.5× solution.

The 3.5× heptane solution was then transferred to a 1L 3-neck jacketedround bottom flask equipped with a mechanical stirrer, a temperaturecontroller, and a nitrogen inlet. The solution was heated at 60° C., andthe resulting homogeneous solution was slowly (1-2 h) cooled to roomtemperature with stirring, further cooled to 0° C. and stirred for 30minutes at the same temperature. The crystals were collected and washedwith ice-cold heptane (200 mL), dried under vacuum at 50° C. to afford apale yellow solid (Compound 5, 85.7 g, 99% pure by GC, 62% yield fromfluoride 1). M.p.: 83° C. (DSC onset temperature) ¹H NMR (400 MHz,CDCl₃) δ 7.85 (1H, d, J=2.5 Hz), 7.48 (1H, d, J=1.7 Hz), 7.38 (1H, d,J=8.3 Hz), 7.31 (1H, dd, J=8.1, 1.8 Hz), 6.33 (1H, d, J=2.5 Hz), 2.30(3H, s); ¹³C NMR (100 MHz, CDCl₃) δ 184.2 (q, J_(C-F)=36.6 Hz), 151.7,138.7, 138.5, 130.7, 126.4, 125.7, 124.5, 116.8, 116.1 (q, J_(C-F)=289.8Hz), 109.7, 13.0; ¹⁹F NMR (376 MHz, CDCl₃) δ=−76.8 (s).

6.2. Preparation of(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol

A 3L 3-neck jacketed round bottom flask equipped with a mechanicalstirrer, a temperature controller, and a nitrogen inlet was chargedsequentially with dichloro(pentamethylcyclopentadienyl)iridium (III)dimer ([Cp*IrCl₂]₂, STREM, CAS#: 12354-85-7, 34 mg, 0.043 mmol),(1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine (STREM,CAS#: 144222-34-4, 32 mg, 0.087 mmol), and water (400 mL, 4×) at roomtemperature. The resulting mixture was stirred for 3 hours at 40° C. togive a homogeneous orange solution. To this active catalyst solution wasadded potassium formate (145.5 g, 1.73 mol) and a solution of the ketone1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone(100 g, >99% purity by GC, 0.346 mol) in CH₃CN (500 mL, 5×) at 40° C.The reaction mixture was then stirred at 40° C. for 2 hours at whichtime the reaction was determined to be complete by GC. After cooling to30° C., the aqueous layer (ca. 480 mL) was removed. The organic layer(ca. 600 mL, 6×) was treated with activated carbon (Darco G-60, 20 g,0.2×) at 45° C. for 2 hours and filtered through ¼ inch bed of CelpureP65 (USP-NF, Pharmaceutical grade, Sigma) and washed with CH₃CN (200 mL,2×). The filtrate was concentrated to 250 mL (2.5×) and transferred to a2 L 3-neck jacketed round bottom flask equipped with a mechanicalstirrer and a temperature controller. More CH₃CN (50 mL, 0.5×) was addedto increase the solution volume to 300 mL (3×). This solution was warmedto 60° C. and water (500 mL, 5×) was added to this solution at the sametemperature. After stirring for 15 minutes at 60° C., the resultingemulsion-like milky mixture was slowly cooled to room temperature. Thecrystals were then filtered at room temperature, and washed withCH₃CN/water (1:2, 150 mL, 1.5×). The wet cake (108 g, KF: 8.83%) wasdried under vacuum at 45° C. for 4 hours to afford the desired alcohol(white solid, 95 g, 94% yield, >99% chemical purity, >99% ee, KF:0.014%). M.p.: 120° C. (DSC onset temperature); ¹H NMR (methanol-d₄, 400MHz) δ 2.19 (br. s., 3H), 5.23 (dd, 6.8 Hz, 7.2 Hz, 1H), 6.19 (d, 2.4Hz, 1H), 7.29 (d, 2 Hz, 1H), 7.42 (dd, 2.0 Hz, 6.4 Hz, 1H), 7.59 (d, 2.4Hz, 1H), 7.68 (d, 8.4 Hz, 1H). ¹³C NMR (methanol-d₄) δ 13.4, 67.2,108.3, 121.7, 124.5, 127.4, 130.1, 131.9, 134.1, 136.4, 141.6, 152.3.LC/MS: MH⁺=291.

6.3. Preparation of (S)-methyl2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethylsulfonyloxy)phenyl)propanoate

This compound was prepared based on a literature procedure (Shieh, etal., J. Org. Chem. 57:379-381 (1992)). To a solution of Boc-Tyr-OMe(Bachem, Calif., 100 g, 0.34 mol) and N-methylmorpholine (51 g, 1.5 eq)in dichloromethane (1000 ml) was added triflic anhydride (100 g, 1.05eq) over 2 hours at −5 to −15° C. The resulting red solution was stirredat −10° C. for 10 minutes. HPLC analysis showed complete disappearanceof starting material. The reaction was quenched with 10% citric acid(500 ml). The organic layer was washed with 10% citric acid (500 ml)followed by water (500 ml). The resulting light pink solution wasconcentrated under reduced pressure to 200 ml. This was diluted withacetonitrile (600 ml) and further concentrated to a 200 g solution. Thissolution was used in the next step without further purification.Estimated yield was 98% by stripping a sample to dryness to give a lowmelting pale yellow solid. LC-MS (ESI): MH⁺=428.0, MNH₄ ⁺=445.0. ¹H NMR(CDCl₃) δ 7.16 (m, 4H), 4.95 (d, J=7.1 Hz, 1H), 4.53 (m, 1H), 3.64 (s,3H), 3.10 (dd, J₁=5.7 Hz, J₂=13.8 Hz, 1H), 2.97 (dd, J₁=6.3 Hz, J₂=13.6Hz, 1H), 1.34 (s, 9H). ¹³C NMR (CDCl₃) δ 172.3, 155.4, 149.0, 137.4,131.5, 121.7, 119.1 (q, J=321 Hz), 80.54, 54.62, 52.7, 38.3, 28.6. ¹⁹FNMR (CDCl₃) δ-73.4.

6.4. Preparation of (S)-methyl2-(tert-butoxycarbonylamino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

This compound was prepared based on a literature procedure (Firooznia,et al., Tetrahedron Lett. 40:213-216 (1999)). Bis(pinacolato)diboron (90g, 1.1 eq), potassium acetate (63 g, 2 eq), tricyclohexylphosphine (2.3g, 2.5 mol %), and palladium acetate (0.72 g, 1 mol %) were mixed inacetonitrile (950 ml) and the resulting mixture stirred at roomtemperature (r.t.) for 5 minutes. (S)-Methyl2-(tert-butoxycarbonylamino)-3-(4-(trifluoromethylsulfonyloxy)-phenyl)propanoatesolution (190 g, 0.32 mol) was added and the resulting mixture washeated at 80° C. for 1 hours and cooled. HPLC showed completeconsumption of the starting material. The reaction mixture was quenchedwith aqueous potassium bicarbonate solution (57 g in 475 ml water) andthe resulting mixture was stirred at r.t. for 30 minutes. The mixturewas filtered through a pad of 20 micron cellulose to remove palladiumblack. A sample of the organic layer was concentrated and purified bycolumn chromatography (gradient: 1:10 to 1:4 ethyl acetate/hexanes) togive the ester compound as a clear oil. LC-MS (ESI): MH⁺=406.2, MNH₄⁺=423.2, M₂H⁺=811.5, M₂NH₄ ⁺=428.5. ¹H NMR (CDCl₃) δ 7.76 (d, J=8.1 Hz,2H), 7.15 (d, J=7.6 Hz, 2H), 4.96 (d, J=7.3 Hz, 1H), 4.60 (m, 1H), 3.72(s, 3H), 3.13 (m, 2H), 1.44 (s, 9H), 1.36 (s, 12H).

The above organic layer of the ester was stirred with aqueous lithiumhydroxide solution (23 g in 500 mL water) at r.t. for 30 minutes. The pHof the resulting slurry was adjusted to about 10 with 6 N hydrochloricacid and filtered. The cake was washed with water (200 mL). Acetonitrilewas removed from the filtrate under reduced pressure to give an aqueousslurry (950 mL, additional water was added during distillation). Theslurry was filtered through a pad of 20 micron cellulose and washed withwater (200 mL). The filtrate was washed with MTBE (500 mL) and redilutedwith 700 mL MTBE. The mixture was acidified to pH about 4.5 with 6 Nhydrochloric acid. The organic layer was washed with water (500 mL) andconcentrated under reduced pressure to the acid compound as a brown oil(206 g, 95% yield based on estimated purity by NMR). The crude productcan be used directly in the following step. Alternatively, the compoundcan be purified by crystallization from MTBE/heptane to give a whitesolid, which contains a small amount of the corresponding boronic acid,(S)-3-(4-boronophenyl)-2-(tert-butoxycarbonylamino)propanoic acid. MS(ESI): MH⁺=392.2, MNH₄ ⁺=409.2, M₂H⁺=783.4, M₂NH₄ ⁺=800.4. ¹H NMR(CDCl₃) δ 7.95 (br s, 1H), 7.76 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.6 Hz,2H), 5.03 (d, J=7.8 Hz, 1H), 4.62 (m, 1H), 3.18 (m, 2H), 1.43 (s, 9H),1.35 (s, 12H). ¹³C NMR (CDCl₃) δ 175.8, 155.7, 139.7, 135.4, 129.2,84.2, 80.5, 54.5, 38.3, 28.7, 25.2.

6.5. Preparation of(S)-3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid

To a 2L 3-neck round bottom flask equipped with a mechanical stirrer anda temperature controller was added (S)2-(tert-butoxycarbonylamino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoicacid (30.3 g, 0.078 mol), 2-amino-4,6-dichloropyrimidine (38.03 g, 3.0eq), catalyst POPd6 (0.605 g, 1.0 mol %, CombiPhos Catalysts, Inc., NewJersey) and ethanol (728 mL). To the above stirring slurry was thenadded aqueous potassium bicarbonate solution (27.85 g, 3.5 eq, in 173 mLH₂O) slowly so that CO₂ gas evolution was not vigorous. This mixture washeated at 75° C. for 6 hours, at which time HPLC analysis showed greaterthan 99% conversion of the starting material. Ethanol was removed fromthe mixture under reduced pressure to give an aqueous slurry (˜200 mL),additional H₂O (90 mL) was added and the solution was concentrated to˜250 mL. Water (90 mL) was added to the slurry, which was then filteredand washed with water (60 mL×2). The filtrate was extracted with ethylacetate (150 mL). The aqueous solution was treated with Darco-G60 (6.0g) at 60° C. for 2 hours, filtered through celite (Celpure 300, 10 g),and diluted with THF (240 mL) and toluene (180 mL). 6N HCl was slowlyadded to the mixture at room temperature until the pH reached 4.0. Theorganic layer was separated and washed with water (180 mL), andDarco-G60 (6.0 g) was added: the resulting mixture was heated at 60° C.for 2 hours. The solution was cooled to room temperature and filteredthrough celite (Celpure 300, 10 g). The cake was washed with THF (30mL×2). The resulting solution was concentrated under vacuum to ˜180 mLoverall volume, at which point, the product precipitated out ofsolution. The slurry was then cooled to room temperature, filtered andthe cake was washed by toluene (30 mL×2). The solid was oven-dried undervacuum at 50° C. overnight to give 24.0 g of product as a light yellowsolid which by ¹H NMR contained ˜8.0 wt % of toluene in 75% (corrected)yield. HPLC showed 91% purity with 9.0% of diacid impurity.

6.6. Alternative Procedure for Preparation of(S)-3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid from (S)-2-amino-3-(4-boronophenyl)propanoic Acid Using PotassiumCarbonate as Base

(S)-2-Amino-3-(4-boronophenyl)propanoic acid (Ryscor Science, Inc.,North Carolina, 1.0 g, 4.8 mmol) and potassium carbonate (1.32 g, 2 eq)were mixed in aqueous ethanol (15 ml ethanol and 8 ml water).Di-tert-butyldicarbonate (1.25 g, 1.2 eq) was added in one portion.After 30 minutes agitation at r.t., HPLC analysis showed completeconsumption of the starting compound and formation of(S)-3-(4-boronophenyl)-2-(tert-butoxycarbonylamino)propanoic acid. The2-amino-4,6-dichloropyrimidine (1.18 g, 1.5 eq) and the catalystbis(triphenylphosphine)palladium(II) dichloride (34 mg, 1 mol %) wereadded and the resulting mixture was heated at 65-70° C. for 3 hours.HPLC analysis showed complete consumption of the intermediate,(S)-3-(4-boronophenyl)-2-(tert-butoxycarbonylamino)propanoic acid. Afterconcentration and filtration, HPLC analysis of the resulting aqueoussolution against a standard solution of the title compound showed 1.26 g(67% yield).

6.7. Alternative Procedure for Preparation of(S)-3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicAcid from (S)-2-amino-3-(4-boronophenyl)propanoic Acid Using PotassiumCarbonate/Potassium Bicarbonate as Base

(S)-2-Amino-3-(4-boronophenyl)propanoic acid (10 g, 48 mmol) andpotassium bicarbonate (14.4 g, 3 eq) were mixed in aqueous ethanol (250ml ethanol and 50 ml water). Di-tert-butyldicarbonate (12.5 g, 1.2 eq)was added in one portion. HPLC analysis indicated that the reaction wasnot complete after overnight stirring at r.t. Potassium carbonate (6.6g, 1.0 eq) and additional di-tert-butyldicarbonate (3.1 g, 0.3 eq) wereadded. After 2.5 hours agitation at r.t., HPLC analysis showed completeconsumption of the starting compound and formation of(S)-3-(4-boronophenyl)-2-(tert-butoxycarbonylamino)propanoic acid. The2-amino-4,6-dichloropyrimidine (11.8 g, 1.5 eq) and the catalystbis(triphenylphosphine)-palladium(II) dichloride (0.34 g, 1 mol %) wereadded and the resulting mixture was heated at 75-80° C. for 2 hours.HPLC analysis showed complete consumption of the intermediate,(S)-3-(4-boronophenyl)-2-(tert-butoxycarbonylamino)propanoic acid. Themixture was concentrated under reduced pressure and filtered. Thefiltrate was washed with ethyl acetate (200 ml) and diluted with 3:1THF/MTBE (120 ml). This mixture was acidified to pH about 2.4 by 6 Nhydrochloric acid. The organic layer was washed with brine andconcentrated under reduced pressure. The residue was precipitated inisopropanol, filtered, and dried at 50° C. under vacuum to give thetitle compound as an off-white solid (9.0 g, 48% yield). Purity: 92.9%by HPLC analysis. Concentration of the mother liquor yielded andadditional 2.2 g off-white powder (12% yield). Purity: 93.6% by HPLCanalysis.

6.8. Alternative Procedure for Preparation of(S)-3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicAcid from (S)-2-amino-3-(4-boronophenyl)propanoic Acid Using a Mixtureof Palladium Acetate and Triphenylphosphine as Catalyst

To a reactor was charged ethanol (330 kg), (S)2-(tert-butoxycarbonylamino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoicacid (55 kg), 2-amino-4,6-dichloropyrimidine (70 kg), triphenylphosphine(0.55 kg), palladium acetate (0.24 kg), and THF (720 kg). To thismixture was slowly charged aqueous potassium hydrogen carbonate solution(50.1 kg in 320 kg water). The resulting mixture was heated at 68˜72° C.for 20-23 hours and cooled. Ethanol was replaced by water by repeatedvacuum distillations and dilutions with water. Insolubles were filteredat room temperature and wet cake washed with water. The filtrate waswashed with ethyl acetate twice. The aqueous layer was mixed with THF(664 kg) and toluene (512 kg) and the pH was adjusted to about 2.5-3.5by 6 N HCl. The aqueous layer was extracted with ethyl acetate twice.The combined organic layers were treated with charcoal at 40-50° C. andfiltered through a pad of cellulose and sodium sulfate. The cake waswashed with 1:1 THF/toluene. The filtrate was concentrated and theproduct was crystallized from toluene/THF. After drying at 40-45° C.under vacuum,(S)-3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid toluene solvate was obtained as an off-white solid (65% yield).

6.9. Preparation of (S)-Ethyl2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate

A 500 mL 3-neck round bottom flask equipped with a mechanical stirrer, atemperature controller, and a condenser was charged with themonochloride(S)-3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid (20.0 g, 51 mmol),(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(>99% ee, 16.3 g, 56 mmol, 1.1 equiv.), Cs₂CO₃ (24.9 g, 76 mmol, 1.5equiv.), and anhydrous 1,4-dioxane (150 mL, 7.5×, KF=0.003%). Themixture was stirred under nitrogen and the temperature was increased to100° C. with good stirring. The reaction mixture was stirred at 100° C.for 1 hour and additional Cs₂CO₃ (33.2 g, 102 mmol, 2.0 equiv.) wasadded. The reaction mixture was then stirred for 18 hours at 100° C. Theheterogeneous reaction mixture was cooled to 90° C. and water (150 mL,7.5×) was added with good stirring. The mixture was cooled to roomtemperature.

To the biphasic solution was added Di-tert-butyl dicarbonate (1.11 g,5.1 mmol, 0.1 equiv.) at room temperature and stirred for 2 hours at thesame temperature. Toluene (100 mL, 5×) was added, the resulting mixturewas stirred for 15 minutes at room temperature, and the phases weresplit. Water (100 mL, 5×) was added to the organic layer, and theresulting mixture was stirred for 15 minutes at room temperature, andthe phases were split. The aqueous layer (pH=10.5) was then acidified topH 7-6 using 6 N HCl at room temperature. EtOAc (100 mL, 5×) was addedto this mixture, and further acidification to pH 4 was carried out using6 N HCl at room temperature with good stirring. After splitting theorganic layer, the aqueous layer was extracted with EtOAc (100 mL, 5×).The combined organic layers were washed with brine (100 mL, 5×). TheEtOAc layer was then concentrated under vacuum to a total volume ofabout 40 mL (2×). EtOH (100 mL, 5×) was added, and concentrated to 2×solution. The EtOH (150 mL, 7.5×) addition-concentration sequence wasrepeated to give a 2× solution of(S)-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid, which was used directly in the next chemical step. Solution assayshowed that the yield was about 75% from(S)-3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid assuming that the compound's purity was 100%. Analytically pureBoc-acid was obtained by column chromatography and characterized: ¹H NMR(DMSO-d₆, 400 MHz) δ 1.30 (s, 9H), 2.34 (s, 3H), 2.86 (dd, 1H), 3.07(dd, 1H), 4.14 (m, 1H), 6.45 (d, 1H), 6.83 (s, 1H), 7.29 (dd, 1H), 7.33(d, 2H), 7.61 (dd, 1H), 7.75 (d, 1H), 7.99 (d, 2H), 8.21 (d, 1H),12.5-12.8 (br. s., 1H). ¹³C NMR (DMSO-d₆) δ 13.99, 13.89, 22.05, 27.78,28.08, 28.32, 31.21, 36.22, 54.83, 67.41, 67.73, 78.03, 91.15, 107.69,124.99, 125.18, 126.59, 128.12, 129.30, 130.23, 132.69, 134.65, 135.08,140.73, 140.89, 150.41, 155.39, 162.76, 166.17, 168.22, 173.40. Anal.Calcd for C₃₀H₃₀ClF₃N₆O₅: C, 55.69; H, 4.67; N, 12.99. Found: C, 55.65;H, 4.56; N, 12.74.

The above 2× solution was diluted with EtOH (60 mL, 3×) and CH₃CN (100mL, 5×) at room temperature. TBTU (97% pure, Fluka, 19.7 g, 61 mmol, 1.2equiv.) and N-methylmorpholine (6.17 mL, 56 mmol, 1.1 equiv.) were addedto this solution (KF=0.034%) under nitrogen. The resulting solution wasstirred at room temperature for 4 hours. HPLC indicated that theBoc-acid was converted to the Boc-ester (S)-ethyl3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoatequantitatively. The reaction mixture was concentrated to about 2× underreduced pressure (40° C. bath temperature, 100 mbar) and diluted withEtOAc (100 mL, 5×) and water (100 mL, 5×). The organic layer was washedwith saturated aq. KHCO₃ (pH˜8.5) (2×100 mL, 5×) and brine (50 mL,2.5×). This red organic layer was then treated with activated carbon(Darco G-60, 8 g, 0.4×) at 50° C. for 1.5 hours and filtered through ¼inch bed of Celpure P65 (USP-NF, Pharmaceutical grade, Sigma), and thecake washed with CH₃CN (100 mL, 5×). The resulting yellow-coloredfiltrate was concentrated to a 2× solution. CH₃CN (100 mL, 5×) wasadded, and the solution concentrated to a 2× solution. The CH₃CNaddition-concentration sequence was repeated to give a 2× CH₃CN solutionof the Boc-ester which was used directly in the next step. Ananalytically pure Boc-ester was obtained by column chromatography andcharacterized: ¹H NMR (DMSO-d₆, 300 MHz) δ 1.11 (t, J=7.06 Hz, 3H), 1.31(s, 9H), 2.34 (s, 3H), 2.85-3.08 (m, 2H), 4.1-4.2 (m, 1H), 6.45 (d,J=2.29 Hz, 1H), 6.84 (s, 1H), 7.25-7.41 (m, 3H), 7.66 (dd, J=8.58, 2.10Hz, 1H) 7.71 (d, J=2.1 Hz, 1H) 7.80 (d, J=8.58 Hz, 1H) 8.0 (d, J=8.39Hz, 2 H) 8.21 (d, J=2.29 Hz, 1H). ¹³C NMR (DMSO-d₆) δ 13.2, 14.0, 22.1,24.7, 27.7, 28.0, 28.3, 28.4, 31.2, 33.9, 34.1, 36.2, 36.6, 55.0, 56.3,60.4, 67.1, 67.4, 67.7, 68.0, 78.2, 78.5, 91.1, 107.7, 122.1, 125.0,125.2, 126.6, 127.7, 128.1, 129.3, 130.2, 132.7, 134.7, 135.1, 140.4,140.7, 150.4, 154.2, 155.3, 162.8, 166.1, 168.2, 171.9. Anal. Calcd forC₃₂H₃₄ClF₃N₆O₅: C, 56.93; H, 5.08; N, 12.45. Found: C, 57.20; H, 4.86;N, 12.21.

The above 2× solution was diluted with additional CH₃CN (160 mL, 8×) atroom temperature. Methanesulfonic acid (18.4 mL, 255 mmol) was added tothis solution (KF=0.005%) at room temperature, and stirred at 45° C. for1 hours at which time HPLC indicated that the de-Boc reaction iscomplete. The reaction mixture was concentrated to 2×, cooled to 0-5°C., and diluted with ice-cold water (100 mL, 5×) and this aqueoussolution was washed with cold isopropyl acetate twice (IPAc, 100 mL, 5×and 50 mL, 2.5×). The aqueous layer was then basified to pH=6 with 20%aq. Na₂CO₃ at 5° C. with stirring. IPAc (100 mL, 5×) was added to thismixture, and further basification to pH 8.5 was carried out using 20%aq. Na₂CO₃ at room temperature with good stirring. After splitting theorganic layer, the aqueous layer was extracted with IPAc (50 mL, 2.5×).The combined cloudy organic layers were concentrated to a 2× solution.IPAc (100 mL, 5×) was added, and the mixture was concentrated to a 2×solution which contained inorganic salts. The mixture was filtered, andthe solids washed with IPAc (100 mL, 5×), and the filtrate concentratedto a 2× solution. HPLC assay of this clear IPAc solution showed 20.8 gof the title compound (36 mmol, >99% are by HPLC, 71% solution yield).

Analytically pure title compound was obtained by column chromatographyand characterized: ¹H NMR (DMSO-d₆, 400 MHz) δ 1.15 (t, J=7.07 Hz, 3H),2.39 (s, 3H), 2.50 (m, 2H), 3.63 (t, J=6.82 Hz, 1H), 4.07 (q, J=7.07,14.5 Hz, 2H), 6.50 (d, J=2.27 Hz, 2H), 6.87 (s, 1H), 7.33 (m, 3H), 7.65(dd, J=8.59, 2.27 Hz, 1H), 7.71 (d, J=2.27 Hz, 1H), 7.81 (d, J=8.59 Hz,1H) 8.01 (d, J=8.08 Hz, 2H), 8.26 (d, J=2.27 Hz, 1H). ¹³C NMR (DMSO-d₆)δ 13.4, 13.9, 18.5, 21.0, 21.5, 25.4, 55.6, 56.0, 59.9, 66.9, 67.1,67.4, 67.7, 68.0, 91.1, 107.7, 122.1, 124.9, 125.0, 125.2, 126.5, 127.7,128.1, 129.4, 130.2, 132.7, 134.6, 135.1, 140.7, 140.9, 150.4, 162.8,166.2, 168.2, 174.8. Anal. Calcd for C27H26ClF3N6O3: C, 56.40; H, 4.56;N, 14.62. Found: C, 56.51; H, 4.52; N, 14.51.

6.10. Alternative Procedure for Preparation of (S)-Ethyl2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate

To a solution of(S)-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid (2.0 mmol) in ethanol was added thionyl chloride (6 equiv.) at 0°C., and the resulting mixture was stirred for 30 minutes at thistemperature and then at room temperature for 24 hours. HPLC analysisindicated >98% conversion to (S)-ethyl2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

6.11. Alternative Procedure for Preparation of (S)-Ethyl2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate

At a jacket temperature of 20° C. the reactor was charged with(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol(4.23 kg; 1.1 equiv.) and dioxane (52 L; 10 volumes). At 80° C. jackettemperature and reduced pressure (160-150 mbar; corresponding innertemperature: 52-53° C.) 2.5 volumes of dioxane (13 L) were removed bydistillation to remove moisture. The solution was cooled to 20° C.Cesium carbonate (6.52 kg; 1.5 equiv.) was added, and the mixture washeated to 95° C.(S)-3-(4-(2-Amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid (6.95 kg; 1.0 equiv.) was added carefully in portions. The mixturewas heated to 101° C. for 2 hours. After cooling to 95° C., additionalcesium carbonate (8.65 kg; 2.0 equiv.) was added. The reaction mixturewas heated to 101° C. for 24 hours. Water (39 L; 7.5 volumes) was addedand the mixture was quickly cooled to 22° C. Di-t-butyl dicarbonate (289g; 0.1 equiv.) was added, and the mixture was stirred for 2 hours at 22°C. Toluene (26 L; 5 volumes) was added, and the mixture was stirred for15 minutes. The layers were separated (product in organic layer). Water(26 L; 5 volumes) was added to the organic layer and the mixture wasstirred for 15 minutes. The layers were separated (product in aqueouslayer). The pH of the aqueous layer was adjusted to about 7.0 byaddition of HCl 5 N (2 L). Ethyl acetate (26 L; 5 volumes) was added andthe pH was adjusted to 4.0 by addition of HCl 5 N (2 L). The layers wereseparated. The aqueous layer was extracted with ethyl acetate (26 L; 5volumes). The combined organic layers were washed with brine (26 L; 5volumes). The organic layer was concentrated at 65° C. jackettemperature and reduced pressure (230-95 mbar; keeping inner temperaturebelow 40° C.) to 3 vol. Ethanol (31.5 L; 6 volumes) was added anddistilled at 65° C. jacket temperature and reduced pressure (110-100mbar; keeping inner temperature below 40° C.) was continued. 5.5 volumesof solvent were removed by distillation. Ethanol (44 L; 8.5 volumes) wasadded and distillation at 65° C. jacket temperature and reduced pressure(110-100 mbar; keeping inner temperature below 40° C.) was continued toremove 6.5 volumes of solvent.(S)-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid was obtained as an ethanol solution.

Acetonitrile (21 L; 4 volumes) was added to the above, and the solutionwas cooled to 0° C. N-Methyl morpholine (1.614 kg; 1.2 equiv.) wasadded. TBTU (5.32 kg; 1.25 equiv.) was added in portions while keepingthe temperature between 0-5° C. The reaction mixture was stirred at 0°C. for 5 hours, warmed to 40° C. within 6 hours, and stirred foradditional 8 hours at 40° C. At 60° C. jacket temperature and reducedpressure (170-60 mbar; keeping inner temperature below 40° C.) thereaction mixture was concentrated to 3 remaining volumes. Ethyl acetate(26 L; 5 volumes) was added and the mixture was cooled to 22° C. Water(26 L; 5 volumes) was added and the mixture was stirred for 5 minutes.The layers were separated and the organic layer was washed twice withsaturated sodium bicarbonate solution (per portion: 26 L; 5 vol;concentration 7.4%). The organic layer was washed with brine (13 L; 2.5volumes). For color removal, the organic layer was filtrated through aCuno inline filter cartridge ZetaCar-bon R55SP. Reactor and cartridgewere rinsed with acetonitrile (11 L; 2 volumes). At 60° C. jackettemperature and reduced pressure (130-100 mbar; keep inner temperaturebelow 40° C.) the filtrate was concentrated to 2 remaining volumes.Acetonitrile (32 L; 6 volumes) was added and distillation was continued.Six volumes of solvent were removed by distillation at 60° C. jackettemperature and reduced pressure (145-128 mbar; keep inner temperaturebelow 40° C.). A further portion of acetonitrile (32 L; 6 volumes) wasadded and distillation was continued. Six volumes of solvent wereremoved by distillation at 60° C. jacket temperature and reducedpressure (128-116 mbar; keeping inner temperature below 40° C.). Themixture was cooled to 22° C., and acetonitrile (34 L; 6.5 volumes) wasadded. (S)-ethyl3-(4-(2-amino-6-((R)-1′-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoatewas obtained as an acetonitrile solution.

Methanesulfonic acid (4.14 kg; 3.25 equiv.) was added to the abovesolution at 22-32° C. inner temperature within 6 minutes. The additiontank was rinsed with acetonitrile (2.5 L; 0.5 volumes). The reactionmixture was heated to 45° C. within 40 minutes and stirred for 2.5 hoursat this temperature. At 60° C. jacket temperature and reduced pressure(170-140 mbar; keeping inner temperature below 35° C.), 6.9 volumes ofsolvent were removed by distillation. Water (26 L; 5 volumes) was addedcarefully at 0-5° C. (65 minutes). The aqueous solution was washed fourtimes with MTBE (per portion: 16 L; 3 volumes). The aqueous layer wasadded to a solution of potassium carbonate (8.89 kg; 4.85 equiv.) inwater (36 L; 6.8 volumes) and the product was extracted with MTBE (26 L;5 volumes). The aqueous layer was extracted with a second portion ofMTBE (16 L; 3 volumes). The combined organic layers were washed with amixture of water (10.5 L; 2 volumes) and ethanol (1.5 L; 0.3 volumes).At 60° C. jacket temperature and reduced pressure (272-262 mbar; keepinner temperature below 35° C.), the filtrate was concentrated to 3remaining volumes. Ethanol (16 L; 3 volumes) was added and distillationat 60° C. jacket temperature and reduced pressure (206-104 mbar; keepinginner temperature below 35° C.) was continued. Three volumes of solventwere removed. A further portion of ethanol (16 L; 3 volumes) was addedand distillation at 60° C. jacket temperature and reduced pressure(131-89 mbar; keep inner temperature 35° C.) was continued. Threevolumes of solvent were removed. The final solution was cooled to 20° C.and ethanol (10 L; 2 volumes) was added. HPLC assay indicated that theyield of (S)-ethyl2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoatewas 82.6% from(S)-3-(4-(2-amino-6-chloropyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoicacid.

All of the publications (e.g., patents and patent applications)disclosed above are incorporated herein by reference in theirentireties.

1. A method of preparing a compound of formula I:

or a salt thereof, which comprises contacting a compound of formula II:

with a compound of formula III:

under conditions sufficient for the formation of the compound of formulaI, wherein: A₁ is optionally substituted heterocycle; Y₁ is halogen orpseudohalogen; each R₁ is independently amino, halogen, hydrogen,C(O)R_(A), OR_(A), NR_(B)R_(C), S(O₂)R_(A), or optionally substitutedalkyl, alkyl-aryl or alkyl-heterocycle; R₂ is independently amino,halogen, hydrogen, C(O)R_(A), OR_(A), NR_(B)R_(C), S(O₂)R_(A), oroptionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; R₃ ishydrogen, C(O)R_(A), C(O)OR_(A), or optionally substituted alkyl,alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R₄ is hydrogen oroptionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, orheterocycle; each R_(A) is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; each R_(B) isindependently hydrogen or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; each R_(C) is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; and m is 1-4. 2.(canceled)
 3. (canceled)
 4. (canceled)
 5. The method of claim 1, whereinthe compound of formula I is of formula I(a):


6. The method of claim 5, wherein the compound of formula I(a) isformula I(b):

wherein: each R₅ is independently amino, halogen, hydrogen, C(O)R_(A),OR_(A), NR_(B)R_(C), S(O₂)R_(A), or optionally substituted alkyl,alkyl-aryl or alkyl-heterocycle; and n is 1-3.
 7. (canceled) 8.(canceled)
 9. The method of claim 1, wherein R₂ is hydrogen or amino.10. The method of claim 1, wherein R₃ is hydrogen or lower alkyl. 11.The method of claim 1, wherein R₃ is C(O)OR_(A) and R_(A) is alkyl. 12.The method of claim 1, wherein R₄ is hydrogen or lower alkyl.
 13. Themethod of claim 1, wherein R₅ is hydrogen or lower alkyl.
 14. The methodof claim 1, wherein n is
 1. 15. The method of claim 6, wherein thecompound of formula I(a) is (S)-ethyl2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.16. The method of claim 1, wherein the compound of formula II is offormula II(a):


17. The method of claim 16, wherein R₁ is chloro.
 18. The method ofclaim 16, wherein m is
 1. 19. The method of claim 16, wherein thecompound of formula II is(R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.20. (canceled)
 21. (canceled)
 22. (canceled)
 23. The method of claim 1,wherein the compound of formula II is prepared by reducing a compound offormula IV:

24-29. (canceled)
 30. The method of claim 23, wherein the compound offormula IV is1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone.31. The method of claim 23, wherein the compound of formula IV isprepared by reacting a compound of formula V with a trifluoroacetylatingagent under transmetalation conditions

wherein X is bromine or iodine.
 32. The method of claim 31, wherein thecompound of formula V is1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole. 33-36. (canceled)
 37. Amethod of preparing a compound of formula III:

which comprises contacting a compound of formula III(a):

with 2-amino-4,6-dichloropyrimidine and a palladium catalyst underconditions sufficient to provide the compound of formula III, wherein:Y₁ is halogen or pseudohalogen; each R′ is independently hydrogen oroptionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, orheterocycle, or are taken together with the oxygen atoms to which theyare attached to provide a cyclic dioxaborolane; R₂ is independentlyamino, halogen, hydrogen, C(O)R_(A), OR_(A), NR_(B)R_(C), S(O₂)R_(A), oroptionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; R₃ ishydrogen, C(O)R_(A), C(O)OR_(A), or optionally substituted alkyl,alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R₄ is hydrogen oroptionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, orheterocycle; each R_(A) is independently hydrogen or optionallysubstituted alkyl, alkyl-aryl or alkyl-heterocycle; and the palladiumcatalyst is not bis(triphenylphosphine)-palladium(II) chloride.
 38. Themethod of claim 37, wherein Y₁ is chloro.
 39. The method of claim 37,wherein the compound of formula III(a) is of the formula:


40. (canceled)
 41. (canceled)
 42. A method of crystallizing a compoundof formula I:

or a salt thereof, which comprises contacting a compound of formula Iwith a pharmaceutically acceptable amino acid under conditionssufficient to provide a co-crystal of the compound of formula I and theamino acid, wherein: A₁ is optionally substituted heterocycle; each R₁is independently amino, halogen, hydrogen, C(O)R_(A), OR_(A),NR_(B)R_(C), S(O₂)R_(A), or optionally substituted alkyl, alkyl-aryl oralkyl-heterocycle; R₂ is independently amino, halogen, hydrogen,C(O)R_(A), OR_(A), NR_(B)R_(C), S(O₂)R_(A), or optionally substitutedalkyl, alkyl-aryl or alkyl-heterocycle; R₃ is hydrogen, C(O)R_(A),C(O)OR_(A), or optionally substituted alkyl, alkyl-aryl,alkyl-heterocycle, aryl, or heterocycle; R₄ is hydrogen or optionallysubstituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;each R_(A) is independently hydrogen or optionally substituted alkyl,alkyl-aryl or alkyl-heterocycle; each R_(B) is independently hydrogen oroptionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; eachR_(C) is independently hydrogen or optionally substituted alkyl,alkyl-aryl or alkyl-heterocycle; and m is 1-4.
 43. A compound of theformula:


44. A compound of the formula:


45. A compound of the formula:


46. The compound of formula 45, which is of the formula:


47. (canceled)
 48. (canceled)
 49. (canceled)
 50. A compound of theformula:


51. (canceled)
 52. (canceled)
 53. (canceled)
 54. A compound of theformula:


55. (canceled)
 56. (canceled)
 57. (canceled)